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Modulating the Pore Architecture of Ice-Templated Dextran Microparticles Using Molecular Weight and Concentration
Abstract
Spray freeze drying (SFD) is an ice templating method used to produce highly porous particles with complex pore architectures governed by ice nucleation and growth. SFD particles have been advanced as drug carrier systems, but the quantitative description of the morphology formation in the SFD process is still challenging. Here, the pore space dimensions of SFD particles prepared from aqueous dextran solutions of varying molecular weights (40-200 kDa) and concentrations (5-20%) are analyzed using scanning electron microscopy. Coexisting morphologies composed of cellular and dendritic motifs are obtained, which are attributed to variations in the ice growth mechanism determined by the SFD system and modulation of these mechanisms by given precursor solution properties leading to changes in their pore dimensions. Particles with low-aspect ratio cellular pores showing variation of around 0.5-1 μm in diameter with precursor composition but roughly constant with particle diameter are ascribed to a rapid growth regime with high nucleation site density. Image analysis suggests that the pore volume decreases with dextran solid content. Dendritic pores (≈2-20 μm in diameter) with often a central cellular region are identified with surface nucleation and growth followed by a slower growth regime, leading to the overall dendrite surface area scaling approximately linearly with the particle diameter. The dendrite lamellar spacing depends on the concentration according to an inverse power law but is not significantly influenced by molecular weight. Particles with highly elongated cellular pores without lamellar formation show intermediate pore dimensions between the above two limiting morphological types. Analysis of variance and post hoc tests indicate that dextran concentration is the most significant factor in affecting the pore dimensions. The SFD dextran particles herein described could find use in pulmonary drug delivery due to their high porosity and biocompatibility of the matrix material.
... 22 Furthermore, it is possible to prepare porous particles with distinct structures by changing the concentration and components of feed liquid or modifying processing parameters such as lyophilization pressure and temperature (Figure 2). 24 The advantages of preparing BWPs by SFD include preserving stability of sensitive molecules, good flowability, and rapid fluid uptake due to their porous structure. Considering these, we propose SFD as a promising method for preparing in situ gel forming BWPs, BWPs containing nanoparticles, and BWPs based on proteins and peptides such as growth factors. ...
... Scale bars correspond to 10 μm (top row) and 1 μm (bottom row). Adopted with permission from ref.24. Copyright 2022 American Chemical Society. ...
... After freeze drying, more pores on the microparticle surface were left by ice sublimation, and the well-dispersed leucine could also protect the microparticles from absorbing water, facilitating their sphericity and J o u r n a l P r e -p r o o f Journal Pre-proof dispersity. Moreover, compared to dendritic and lamellar pore structure attained at -40 ºC (Fig. 3d3), cellular pore structure was found on the surface of SF-80D-N20D2T1 microparticles (Fig. 3h3), possible ascribing to the rapid growth regime with high nucleation site density [45]. Surprisingly, such phenomenon was not observed in those samples containing Leu (Fig. 3i3 & j3), which could be explained by the rapid precipitation of Leu. ...
Based on the drug repositioning strategy, niclosamide (NCL) has shown potential applications for treating COVID-19. However, the development of new formulations for effective NCL delivery is still challenging. Herein, NCL-embedded dry powder for inhalation (NeDPI) was fabricated by a novel spray freeze drying technology. The addition of Tween-80 together with 1,2-Distearoyl-sn-glycero-3-phosphocholine showed the synergistic effects on improving both the dispersibility of primary NCL nanocrystals suspended in the feed liquid and the spherical structure integrity of the spray freeze dried (SFD) microparticle. The SFD microparticle size, morphology, crystal properties, flowability and aerosol performance were systematically investigated by regulating the feed liquid composition and freezing temperature. The addition of leucine as the aerosol enhancer promoted the microparticle sphericity with greatly improved flowability. The optimal sample (SF-80D-N20L2D2T1) showed the highest fine particle fraction of ~47.83%, equivalently over 3.8 mg NCL that could reach the deep lung when inhaling 10 mg dry powders.
Introduction:
Dry powder inhaler (DPI) formulations are gaining attention as universal formulations with applications in a diverse range of drug formulations. The practical application of DPIs to pulmonary drugs requires enhancing their delivery efficiency to the target sites for various treatment modalities. Previous reviews have not explored the relation between particle morphology and delivery to different pulmonary regions. This review introduces new approaches to improve targeted DPI delivery using novel particle design such as supraparticles and metal-organic frameworks based on cyclodextrin.
Areas covered:
This review focuses on the design of DPI formulations using polysaccharides, promising excipients not yet approved by regulatory agencies. These excipients can be used to design various particle morphologies by controlling their physicochemical properties and manufacturing methods.
Expert opinion:
Challenges associated with DPI formulations include poor access to the lungs and low delivery efficiency to target sites in the lung. The restricted applicability of typical excipients contributes to their limited use. However, new formulations based on polysaccharides are expected to establish a technological foundation for the development of DPIs capable of delivering modalities specific to different lung target sites, thereby enhancing drug delivery.
Handling low-density pharmaceutical products, such as lyophilises, presents a challenge. Spray-freeze-dried (SFD) particles, overcoming many of these challenges, were analysed regarding flowability, mechanical stability, product properties (morphology, particle size) and physicochemical properties of the spraying solution (density, viscosity, freezing point, glass transition). Mannitol-polyvinylpyrrolidone 25 (PVP 25) solutions in concentrations ranging from 2.5 to 20% (w/w) were spray-freeze-dried with three different nozzle-diameters (25, 50, 100 μm). Results show it is not only possible to spray SFD solutions with various physicochemical properties (viscosity ≤3.07 ± 0.04 mPa·s, freezing point depravation ≤1.867 ± 0.058 °C) to produce a free-flowable powder but also the possibility to regulate median particle size via nozzle diameter and solid content of the solution (147–458 μm). All formulations containing at least 0.1 g/ml solid content exhibit a flowability comparable to commercially available excipients products with ten times higher densities with a good or passable flowability (angle of repose ≤40°) and no significant decrease in median particle size after mechanical stability testing (p ≥ 0.05), which can both be attributed to their high average sphericity (> 0.90). This shows that SFD is a suitable method to produce freeze-dried flowable products that maintain their mechanical stability.
Porous scaffolds are widely used in biomedical applications where pore size and morphology influence a range of biological processes, including mass transfer of solutes, cellular interactions and organization, immune responses, and tissue vascularization, as well as drug delivery from biomaterials. Ice templating, one of the most widely utilized techniques for the fabrication of porous materials, allows control over pore morphology by controlling ice formation in a suspension of solutes. By fine‐tuning freezing and solute parameters, ice templating can be used to incorporate pores with tunable morphological features into a wide range of materials using a simple, accessible, and scalable process. While soft matter is widely ice templated for biomedical applications and includes commercial and clinical products, the principles underpinning its ice templating are not reviewed as well as their inorganic counterparts. This review describes and critically evaluates fundamental principles, fabrication and characterization approaches, and biomedical applications of ice templating in polymer‐based biomaterials. It describes the utility of porous scaffolds in biomedical applications, highlighting biological mechanisms impacted by pore features, outlines the physical and thermodynamic mechanisms underpinning ice templating, describes common fabrication setups, critically evaluates complexities of ice templating specific to polymers, and discusses future directions in this field. Ice templating is a simple, accessible, and scalable technique for the fabrication of porous materials. It allows control over pore morphology by controlling ice formation in a material solution, suspension, or slurry. This review describes fundamental principles, fabrication and characterization approaches, and biomedical applications of ice templating in polymer‐based biomaterials.
Understanding the ice recrystallisation inhibition (IRI) activity of antifreeze biomimetics is crucial to the development of the next generation of cryoprotectants. In this work, we bring together molecular dynamics simulations and quantitative experimental measurements to unravel the microscopic origins of the IRI activity of poly(vinyl)alcohol (PVA)—the most potent of biomimetic IRI agents. Contrary to the emerging consensus, we find that PVA does not require a “lattice matching” to ice in order to display IRI activity: instead, it is the effective volume of PVA and its contact area with the ice surface which dictates its IRI strength. We also find that entropic contributions may play a role in the ice-PVA interaction and we demonstrate that small block co-polymers (up to now thought to be IRI-inactive) might display significant IRI potential. This work clarifies the atomistic details of the IRI activity of PVA and provides novel guidelines for the rational design of cryoprotectants.
Herein, the potential of directional freeze‐casting techniques as a very generic, green, and straightforward approach for the processing of various functional porous materials is introduced. These materials include 3D monoliths, films, fibers, and microspheres/beads, which are obtained by the assembly of network building blocks originated from cryoassembly of the various aqueous‐based systems. The process simply relies on 1) directional freezing of the slurry through contact with a cold surface, 2) maintaining the slurry at the frozen state for a particular time with controlling the freezing parameters and directions, and 3) sublimation of the created ice crystal templates inside the developed structure to translate the ice growth pattern to final porous structure. The materials developed with such a cryogenic process contain a highly complex porous structure, e.g., a hierarchical and well‐aligned microstructure in different levels, which renders a high control over the physicochemical and mechanical functionalities. Due to the versatility and controllability of this technique, the process can also be extended for the mimicking of the structures found in natural materials to the bulk materials to assemble bioinspired porous composites with many useful mechanical and physical features. The aim, herein, is to give a brief overview of the recent advances in developing anisotropic porous inorganic, organic, hybrid, and carbonaceous materials with a particular emphasis on materials with biomimicking microstructure using directional ice templating approach and to highlight their recent breakthrough for different high‐performance applications.
Freeze casting, also known as ice templating, is a particularly versatile technique that has been applied extensively for the fabrication of well‐controlled biomimetic porous materials based on ceramics, metals, polymers, biomacromolecules, and carbon nanomaterials, endowing them with novel properties and broadening their applicability. The principles of different directional freeze‐casting processes are described and the relationships between processing and structure are examined. Recent progress in freeze‐casting assisted assembly of low dimensional building blocks, including graphene and carbon nanotubes, into tailored micro‐ and macrostructures is then summarized. Emerging trends relating to novel materials as building blocks and novel freeze‐cast geometries—beads, fibers, films, complex macrostructures, and nacre‐mimetic composites—are presented. Thereafter, the means by which aligned porous structures and nacre mimetic materials obtainable through recently developed freeze‐casting techniques and low‐dimensional building blocks can facilitate material functionality across multiple fields of application, including energy storage and conversion, environmental remediation, thermal management, and smart materials, are discussed.
Developing strategies for the production of porous particles with controllable structures using a spray-drying method has attracted attention of researchers for decades. Although many papers have reported their successful production of porous particles using this method, information on how to create and control the porous structures as well as what parameters involving and what formation mechanism occurring during the synthesis process are still not clear. To meet these demands, the present review covers strategies in the spray-drying developments for the fabrication of porous particles with controllable structure. This information is important for optimizing the production of porous particles with desirable properties. Regulation of process conditions and precursor formulations are also explained, including composition, type, and physicochemical properties of droplet and raw components used (i.e., host component, template, and solvent). The electrostatic interactions between the individual components and the droplets are also presented, while this information tends to be neglected in the conventional spray-drying process. To clarify how the porous particles are designed, current experimental results completed with illustrations for the proposal particle formation mechanism are presented. The review also completed with the opportunities and potential roles of the changing porous structures in practical uses. This review would provide information on how to produce porous particles that can be used for advanced functional materials, such as catalysts, adsorbents, and sensors.
Spray freeze-drying is an evolving technology that combines the benefits of spray-drying and conventional lyophilization techniques to produce drug substance and drug product as free-flowing powders. The high surface-to-volume ratio associated to the submillimeter spray-frozen particles contributes to shorter drying and reconstitution times. The formation of frozen particles is the most critical part of this dehydration technique because it defines the properties of final product. Based on a previously proposed and validated model, the current goal is to understand the role of various controllable parameters in the spray-freezing process. More specifically, given a set of spraying conditions, the model is used to predict the minimum distance required to cool and freeze the droplets below a temperature that prevents coalescence and product agglomeration. A parametric study is carried out to map the operational limit conditions of the actual spray-freezing column apparatus under consideration. For the spray freeze-drying conditions of interest, model simulations indicate that convection contributes to at least 80% of the total droplet heat transfer and, consequently, that freezing column gas temperature and droplet diameter are the most important process parameters affecting the freezing distance.
Freeze casting is a versatile material fabrication process that is known for its ability to createporous scaffold structures from effectively any constituent material. One of its advantagesis that a wide variety of alterations to the processing conditions can result in drastic changesto the final micro- and macro-structure of the freeze-cast scaffolds and, therefore, its prop-erties. Here, the authors present a novel view on these numerous control methods, throughthe concept that each of these methods for controlling freeze casting can either be consid-ered to be an intrinsic or extrinsic control method. Intrinsic control methods act within thefreezing process by altering the characteristic repulsive and attractive forces that governthe interactions between the solid loading particles and approaching freezing front dur-ing freezing of the slurry. Extrinsic control methods act upon the freeze process throughthe application of additional forces or energies, often external to the freezing process. Thisnew system of understanding control over freeze casting is presented so as to inspire newwork on the advanced control of freeze-cast scaffolds, specific work into extrinsic controlmethods and the interactions between intrinsic and extrinsic control methods. © 2018 Brazilian Metallurgical, Materials and Mining Association.
Prothionamide (PTH), a second line antitubercular drug is used to administer in conventional oral route. However, its unpredictable absorption and frequent administration limit its use. An alternate approach was thought of administering PTH through pulmonary route in a form of nanoparticles, which can sustain the release for several hours in lungs. Chitosan, a bio-degradable polymer was used to coat PTH and further freeze dried to prepare dry powder inhaler (DPI) with aerodynamic particle size of 1.76μm. In vitro release study showed initial burst release followed by sustained release up to 96.91% in 24h. In vitro release further correlated with in vivo study. Prepared DPI maintained the PTH concentration above MIC for more than 12h after single dose administration and increased the PTH residency in the lungs tissue more than 24h. Animal study also revealed the reduction of dose in pulmonary administration, which will improve the management of tuberculosis.
A drop of water that freezes from the outside-in presents an intriguing problem: the expansion of water upon freezing is incompatible with the self-confinement by a rigid ice shell. Using high-speed imaging we show that this conundrum is resolved through an intermittent fracturing of the brittle ice shell and cavitation in the enclosed liquid, culminating in an explosion of the partially frozen droplet. We propose a basic model to elucidate the interplay between a steady build-up of stresses and their fast release. The model reveals that for millimetric droplets the fragment velocities upon explosion are independent of the droplet size and only depend on material properties (such as the tensile stress of the ice and the bulk modulus of water). For small (sub-millimetric) droplets, on the other hand, surface tension starts to play a role. In this regime we predict that water droplets with radii below 50 micrometer are unlikely to explode at all. We expect our findings to be relevant in the modeling of freezing cloud and rain droplets.
Scaffolds with potential biological applications having a variety of microstructural and mechanical properties can be fabricated by freezing colloidal solutions into porous solids. In this work, the structural and mechanical properties of TiO2 freeze cast with different soluble additives, including polyethylene glycol, NaOH or HCl, and isopropanol alcohol, are characterized to determine the effects of slurry viscosity, pH, and alcohol concentration on the freezing process. TiO2 powders mixed with water and these different additives are directionally frozen in a mold, then sublimated and sintered to create the porous scaffolds. The different scaffolds are characterized to compare the compressive strength, modulus, porosity, and pore morphology. For all scaffolds, the overall porosity remains constant (80–85%). By changing the concentration of each additive, the lamellar thickness, pore area, and aspect ratio vary significantly, showing inverse relationships to both the compressive strength and modulus. The strength is predicted from the pore aspect ratio of the scaffolds when subjected to compressive loading with the primary failure mode identified as Euler buckling. TiO2 scaffolds freeze cast with different soluble additives are suitable for biomedical applications, such as bone replacements, requiring high porosity and specific pore morphologies.
In this article, we review special features of Gwyddion—a modular, multiplatform, open-source software for scanning probe microscopy data processing, which is available at http://gwyddion.net/. We describe its architecture with emphasis on modularity and easy integration of the provided algorithms into other software. Special functionalities, such as data processing from non-rectangular areas, grain and particle analysis, and metrology support are discussed as well. It is shown that on the basis of open-source software development, a fully functional software package can be created that covers the needs of a large part of the scanning probe microscopy user community.
Antifreeze proteins (AFPs) are able to influence the ice crystal growth and the recrystallization process due to the Gibbs-Thomson effect. The binding of the AFP leads to the formation of a curved ice surface and it is generally assumed that there is a critical radius between the proteins on the ice surface that determines the maximal thermal hysteresis. Up to now, this critical radius has not yet been proven beyond doubt or only in poor agreement with the Gibbs-Thomson equation. Using molecular dynamics (MD) simulations, the resulting three-dimensional surface structure is analyzed and the location of the critical radius is identified. Our results demonstrate that the correct analysis of the geometry of the ice surface is extremely important and cannot be guessed upfront a simulation. In contrary to earlier expectations from the literature, we could show that the critical radius is not located directly between the adsorbed proteins. In addition, we showed that the minimum temperature at which the system does not freeze is in very good agreement with the value calculated with the Gibbs-Thomson equation at the critical radius, as long as dynamic system conditions are taken into account. This proves on the one hand that the Gibbs-Thomson effect is the basis of thermal hysteresis and that MD simulations are suitable for the prediction of the melting point depression.
Many types of porous particles containing inorganic and organic substances, such as carbon, metals, metal oxides, inorganic-organic hybrids, and polymers, have been developed. However, natural polymer-derived particles are relatively rare. To our knowledge, this report describes the first synthetic method for obtaining meso-/macroporous particles made from pectin, which is a natural polymer with a wide range of biological activities suitable for active substance support applications. These porous particles were prepared using a template-assisted spray-drying method, followed by a chemical etching process. An organic template [i.e., poly(methyl methacrylate) (PMMA)] or an inorganic template [i.e., calcium carbonate (CaCO3)] was used to evaluate the resulting formation of macroporous structures in the pectin particles. Furthermore, the concentration of the templates in the precursor solution was varied to better understand the mechanism of porous pectin particle formation. The results showed that the final porous particles maintained the characteristic properties of pectin. The differences between the two templates resulted in two distinct types of porous particles that differed in their particle morphologies (i.e., spherical or wrinkled), particle sizes (ranging from 3 to 8 μm), pore sizes (ranging from 80 to 350 nm), and pore volume (ranging from 0.024 to 1.40 cm3 g-1). Especially, the porous pectin particles using the CaCO3 template have a significantly high specific surface area of 171.2 m2 g-1, which is 114 times higher than that of nonporous pectin particles. These data demonstrated the potential for using PMMA and CaCO3 templates to control and design desired porous materials.
The tailored synthesis of carbon particles with controllable shapes and structures from biomass as a raw material would be highly beneficial to meet the demands of various applications of carbon materials from the viewpoint of sustainable development goals. In this work, the spherical carbon particles were successfully synthesized through a spray drying method followed by the carbonization process, using Kraft lignin as the carbon source and potassium hydroxide (KOH) as the activation agent. As the results, the proposed method successfully controlled the shape and structure of the carbon particles from dense to hollow by adjusting the KOH concentration. Especially, this study represents the first demonstration that KOH plays a crucial role in the formation of particles with good sphericity and dense structures. In addition, to obtain an in-depth understanding of the particle formation of carbon particles, a possible mechanism is also investigated in this article. The resulting spherical carbon particles exhibited dense structures with a specific surface area (1233 m² g⁻¹) and tap density (1.46 g cm⁻³) superior to those of irregular shape carbon particles.
Co-loaded isoniazid and pyrazinamide chitosan nanoparticles were formulated using the ionic gelation method. The formulations were adjusted to five mass ratios of tripolyphosphate (TPP) and chitosan at three TPP concentrations. Particle size, polydispersity index, zeta potential, and encapsulation efficiency were used to evaluate all formulations. The results revealed that the ratio of TPP to chitosan had the highest impact in generating chitosan nanoparticles. The selected nanoparticle formulations were freeze-dried, and the obtained dry powders were characterized using scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy to confirm the interaction of loaded drug and formulation excipients. The aerosolized performance of dry powders was also evaluated using the Andersen cascade impactor. A mass median aerodynamic diameter of 3.3–3.5 µm, % fine particle fraction of 30–44%, and 92–95% emitted dose were obtained from all formulations. The dry powder formulations were not toxic to the respiratory tract cell lines. Furthermore, they did not provoke alveolar macrophages into producing inflammatory cytokines or nitric oxides, indicating that the formulations are safe and could potentially be used to deliver to respiratory tract for tuberculosis treatment.
The antifreeze activity of a type III antifreeze protein (AFP) expressed in ocean pout (Zoarces americanus) is compared with that of a specific mutant (T18N) using all-atom molecular dynamics simulations. The antifreeze activity of the mutant is only 10% of the wild-type AFP. The results from this simulation study revealed the following insights into the mechanism of antifreeze action by type-III AFPs. The AFP gets adsorbed to the advancing ice front due to its hydrophobic nature. A part of the hydrophobicity is caused by the presence of clathrate structure of water molecules near the ice-binding surface (IBS). The mutation in the AFP disrupts this structure and thereby reduces the ability of the mutant to adsorb to the ice-water interface leading to the loss of antifreeze activity. The mutation, however, has no effect on the ability of the adsorbed protein to bind to the growing ice phase. The simulations also revealed that all surfaces of the protein can bind to the ice phase, although, the IBS is the preferred surface.
Significance
From critically affecting the performance of an aircraft to droplet-based additive manufacturing, the solidification of impacting droplets influences a wide range of industrial applications; thus, a deeper fundamental understanding of the solidification of an impacting droplet is necessary. In this work, we reveal and rationalize a peculiar freezing morphology originating from the complex interplay between the droplet-scale hydrodynamics and phase-transition effects at sufficiently high substrate undercooling. The direct visualization of different freezing morphologies only became possible as we adopt an optical technique (TIR) in the context of freezing. This technique can be employed in more complex situations, such as solidification of an impacting droplet on liquid-infused or patterned surfaces, which potentially can influence many industrial processes.
Compared with oral and parenteral formulations, inhaled formulations are attractive because of their great benefit and potential to enhance therapeutic effects of medications. Among the available inhaled formulations, powders used with dry-powder inhalers (DPIs) have become a preferred option because of their many advantages over other inhaled formulations. Additionally, a powder technological approach is required and available for sophisticated design of DPI formulations. To provide appropriate treatment using a DPI formulation, inhaled particles containing drugs should be delivered to the appropriate sites in the lungs of individual patients. It is indispensable that the design of DPI formulations specify particle properties suitable for a specific disease and the appropriate positions in the lungs to which the inhaled particles must be delivered. This article focuses on the current particle technological approach toward designing DPI formulations and numerical simulation analysis of behavior and deposition of inhaled particles in the lungs. As a future perspective from the viewpoint of pharmaceutical particle technology, a combination of experimental and simulation approaches is expected to improve the ability to obtain maximum lung delivery as well as target the site of deposition in the lungs of individual patients.
Spray freeze drying is relatively a recent drying technique involving heterogeneous set of steps which includes droplet formation, freezing, and sublimation. It has proven benefits over other drying methods in terms of producing products with improved structural integrity, superior quality, and better shelf stability. With such merits, spray freeze drying has found numerous applications in the field of drug delivery. Spray freeze drying yields particles of sizes and densities that show higher stability in the lungs, nasal mucosa, intestine, and skin, as compared to other drying technologies. These particles also possess the vital trait of sustained release and specificity through various delivery routes as compared to conventional drying techniques. This drives the market for commercialization of spray freeze dried drugs. The focus of this paper is on manufacturing approaches of spray freeze dried powders, with emphasis on its application in drug delivery systems. An overview of other applications of spray freeze drying is also presented.
This study aimed to develop a dry powder inhaler (DPI) formulation for enhanced deep lung delivery of rifampicin using dextrans of different molecular weights. Porous particles were formed by a spray-drying method, which was designed based on the Peclet number. The morphology of particles containing both rifampicin and dextran was dependent on the dextran concentration. The D50 values of SDPs containing rifampicin and dextran 40 or 70 at ratios of less than 1:10 were below 5 μm. The specific surface area values of spray-dried particles containing rifampicin and dextran 40 or 70 of more than 1:10 were over 20 m²/g, assuming that an increase in specific surface area was indicative of an increase in the formation ratio of a porous structure. DPI formulations that contained higher amounts of dextran had higher rifampicin contents. Thus, the formulations containing a dextran: rifampicin ratio of 1:20 had approximately 100% drug encapsulation.
The formation of the porous particles can be explained by the related Peclet number, which correlates with the viscosity and surface tension of the ethanol-water solution used in preparing the particles. It was noted that the existence ratio of the porous particles increased as the viscosity of the mixed solution was increased. Furthermore, an increase in the proportion of dextran resulted in higher rifampicin loading into the particles and the formation of finer particle fractions (FPF) (<7.0 μm at a rate of 28.3 L/min, <4.8 um at a rate of 60.0 L/min). The formulations containing rifampicin and both dextrans at a ratio of more than 1:10 consisted of approximately 50% FPF at a rate of 28.3 L/min and 60.0 L/min. The results indicate that dextran is suitable to obtain porous particles via spray-drying. Additionally, the existence ratio of the porous particles can be improved by increasing the viscosity of the solution used in the preparation of the particles.
Ice-binding Proteins (IBPs) bind to ice crystals and control their growth, enabling host organisms to adapt to sub-zero temperatures. By binding to ice, IBPs can affect the shape and recrystallization of ice crystals. The shape of ice crystals produced by IBPs varies, and is partially due to which ice planes the IBPs are bound. Previously we have described a bacterial IBP found in the metagenome of the symbionts of Euplotes focardii (EfcIBP). EfcIBP shows remarkable ice recrystallization inhibition activity. As recrystallization inhibition of IBPs and other materials are important to the cryopreservation of cells and tissues, we speculate that the EfcIBP can play a future role as an ice recrystallization inhibitor in cryopreservation applications. Here we show that EfcIBP results in a Saturn-shaped ice burst pattern, which may be due to the unique ice-plane affinity of the protein that we elucidated using the fluorescent-based ice-plane affinity analysis. EfcIBP binds to ice at a speed similar to that of other moderate IBPs (5 ± 2 mM⁻¹ s⁻¹); however, it is unique in that it binds to the basal and a previously unobserved pyramidal near-basal planes, while other moderate IBPs typically bind to the prism and pyramidal planes, however not basal or near-basal planes. These insights into EfcIBP allow a better understanding of the recrystallization inhibition for this unique protein.
We use single particle tracking to investigate colloidal dynamics in hybrid assemblies comprising colloids enmeshed in a crosslinked polymer network. These assemblies are prepared using ice templating and are macroporous monolithic structures. We investigate microstructure-property relations in assemblies that appear chemically identical, but show qualitatively different mechanical response. Specifically, we contrast elastic assemblies that can recover from large compressive deformations with plastic assemblies that fail on being compressed. Particle tracking provides insights into the microstructural differences that underlie the different mechanical response of elastic and plastic assemblies. Since colloidal motions in these assemblies are sluggish, particle tracking is especially sensitive to imaging artifacts such as stage drift. We demonstrate that the use of wavelet transforms applied to trajectories of probe particles from fluorescence microscopy eliminates stage drift, allowing a spatial resolution of about 2 nm. In elastic and plastic scaffolds, probe particles are surrounded by other particles – thus, their motion is caged. We present mean square displacement and van Hove distributions for particle motions and demonstrate that plastic assemblies are characterized by significantly larger spatial heterogeneity when compared with the elastic sponges. In elastic assemblies, particle diffusivities are peaked around a mean while in plastic assemblies, there is a wide distribution of diffusivities with no clear peak. Both elastic and plastic assemblies show a frequency independent solid modulus from particle tracking microrheology. Here too, there is a much wider distribution of modulus values for plastic scaffolds as compared to elastic, in contrast to bulk rheological measurements where both assemblies exhibit a similar response. We interpret our results in terms of the spatial distribution of crosslinks in the polymer mesh in the colloidal assemblies.
Ice formation is a ubiquitous process that poses serious challenges for many areas. Nature has evolved a variety of different mechanisms to regulate ice formation. For example, many cold-adapted species produce antifreeze proteins (AFPs) and/or antifreeze glycoproteins (AFGPs) to inhibit ice recrystallization. Although several synthetic substitutes for AF(G)Ps have been developed, the fundamental principles of designing AF(G)P mimics are still missing. In this study, we explored the molecular dynamics of ice recrystallization inhibition (IRI) by poly(vinyl alcohol) (PVA), a well-recognized ice recrystallization inhibitor, to shed light on the otherwise hidden ice-binding mechanisms of chain polymers. Our molecular dynamics simulations revealed a stereoscopic, geometrical match between the hydroxyl groups of PVA and the water molecules of ice, and provided microscopic evidence of the adsorption of PVA to both the basal and prism faces of ice and the incorporation of short-chain PVA into the ice lattice. The length of PVA, i.e., the number of hydroxyl groups, seems to be a key factor dictating the performance of IRI, as the PVA molecule must be large enough to prevent the joining together of adjacent curvatures in the ice front. The findings in this study will help pave the path for addressing a pressing challenge in designing synthetic ice recrystallization inhibitors rationally, by enriching our mechanistic understanding of IRI process by macromolecules.
Cold acclimatized organisms produce antifreeze proteins that enable them to prevent ice growth and recrystallization at subfreezing conditions. Flatness and rigidity of the ice-binding sites of antifreeze proteins are considered key for their recognition of ice. However, the most potent synthetic ice recrystallization inhibitor (IRI) found to date is polyvinyl alcohol (PVA), a fully flexible molecule. The ability to tune the architecture and functionalization of PVA makes it a promising candidate to replace antifreeze proteins in industrial applications ranging from cryopreservation of organs to deicing of turbine blades. However, an understanding of how does PVA recognize ice remains elusive, hampering the design of more effective IRIs. Here we use large-scale molecular simulations to elucidate the mechanism by which PVA recognizes ice. We find that the polymer selectively binds to the prismatic faces of ice through a cooperative zipper mechanism. The binding is driven by hydrogen bonding, facilitated by distance matching between the hydroxyl groups in PVA and water at the ice surface. Strong, cooperative binding to ice results from the different scaling of the free energy gains on binding per monomer, and the loss of translational and configurational entropy of the chain. We explain why branching of PVA does not improve its IRI activity, and use the new molecular understanding to propose principles for the design of macromolecules that bind efficiently to the basal and prismatic planes of ice, producing hyperactive synthetic antifreeze molecules that could compete with the most effective antifreeze proteins.
Nanocomposite microparticle (nCmP) systems exhibit promising potential in the application of therapeutics for pulmonary drug delivery. This work aimed to identify the optimal spray drying condition(s) to prepare nCmP with specific drug delivery properties including: small aerodynamic diameter, effective nanoparticle redispersion upon nCmP exposure to an aqueous solution, high drug loading, and low water content. Acetalated dextran (Ac-Dex) was used to form nanoparticles, curcumin was used as a model drug, and mannitol was the excipient in the nCmP formulation. Box–Behnken design was applied using Design-Expert software for nCmP parameter optimization. Nanoparticle ratio (NP%) and feed concentration (Fc) are significant parameters that affect the aerodynamic diameters of nCmP systems. NP% is also a significant parameter that affects the drug loading. Fc is the only parameter that influenced the water content of the particles significantly. All nCmP systems could be completely redispersed into the parent nanoparticles, indicating that none of the factors have an influence on this property within the design range. The optimal spray drying condition to prepare nCmP with a small aerodynamic diameter, redispersion of the nanoparticles, low water content, and high drug loading is: 80% nanoparticle ratio, 0.5% feed concentration, and an inlet temperature lower than 130°C.
This work aims to identify a suitable formulation for the pulmonary delivery of combinations of inhalational drugs using highly branched cyclic dextrin (HBCD) macromolecules. We compared the effectiveness between powders prepared from HBCD with those prepared from five alternative excipients (lactose, maltose, sucrose, β-cyclodextrin and methyl β-cyclodextrin) in the pulmonary delivery of a single-dosage form of two anti-tuberculosis drugs (isoniazid and rifampicin).
Fine particles of untreated active pharmaceutical ingredients (APIs) and combination products using excipients were prepared by spray drying. Rifampicin, a hydrophobic compound, was dissolved in ethanol, whereas isoniazid, a hydrophilic compound combined with either HBCD or an alternative excipient was dissolved in water. This was followed by the preparation of the spray-dried particle formulations (SDPs). The SDPs were characterised in terms of particle size, surface morphology, drug content, specific surface area, powder X-ray diffraction and inhalational properties.
The addition of either an excipient or HBCD decreased API particle sizes, producing submicron-size particles. Surface morphology examination using scanning electron microscopy revealed API SDPs to be cylindrical and non-wrinkled. However, API–excipient SDPs were wrinkled and rough. Only HBCD SDPs were porous and non-aggregating, thereby suggesting superior aerodynamic properties and suitability for pulmonary delivery of these particles. HBCD formulations had the highest drug content in terms of both isoniazid (97.5%) and rifampicin (92.3%). Larger surface areas were obtained for SDPs of HBCD than those of other sugars. Regarding inhalational properties, HBCD formulations had higher emitted dose and fine-particle fractions than formulations of all other sugars tested. Our results confirm the feasibility of the formulation of hydrophilic and hydrophobic drug substances into a single-dosage preparation for pulmonary delivery using HBCD as an excipient.
Powders of nanoparticles are volatile, i.e. easily disperse in air, which makes their handling difficult. Granulation of nanoparticle powders provides a solution to that issue, and it is generally performed by spray drying the nanoparticles that have been suspended in a liquid. Spray drying of a colloidal suspension consists of atomising the suspension into droplets by a fast flowing and hot gas. Once the droplets dried, the resulting dry grains/microparticles can be used in a wide range of applications - food, pharmaceutics, fillers, ceramics, etc. It is well known that the grains resulting from spray-drying may be spherical but may also exhibit other diverse morphologies. Although different influencing parameters have been identified, no clear overview can be found in the literature for the driving mechanisms of grain shaping. In the present work, we review the assumptions made in the literature to explain the different morphologies. We analyse the orders of magnitude of the different effects at stake and show that the grain shape does not result from a hydrodynamic instability but is determined by the drying stage. However, we emphasize that neither the drying time nor the associated Péclet number are critical parameters for the determination of shape morphology. In light of those results, we also review and discuss the single droplet experiments developed to mimic spray drying. Generalising our previous works, we further analyse how the control of morphology can be achieved by tuning the colloidal interactions in the suspension. We detail the model we have developed that relates the colloidal interaction potential to a critical pressure exerted by the solvent as it flows, and we provide a quantitative prediction of the grain shape. Finally, we offer perspectives with regard to spray drying of systems such as molecular solutions, widely performed in e.g. the pharmaceutical industry.
Hydroxyapatite (HA) porous scaffolds with bionic bone graded structure were fabricated by a two-step freeze casting. The phase, porosity, pore morphology, and compressive strength of the fabricated HA scaffolds were characterised. The HA scaffolds did not decompose after sintering at 1250 °C. The porosity of the inside and outside of the graded-porosity HA scaffolds was controlled by adjusting the initial HA content of the casting slurries. Cylindrical HA scaffolds with a radially aligned porosity gradient from the inside (highly porous) to the outside (less porous) were prepared, and a natural transition was found at the interface because partial melting-recrystallization occurred between the two sides. The compressive strength of the graded HA scaffolds depended on the porosity of the inner part. A compressive strength of 22.2±4.1 MPa was achieved at an average porosity of 42.3% and outer thickness of about 2 mm.
Effective delivery of drugs to alveoli in a controlled manner using hydrophobic polymers as carriers has already been reported. Preclinical studies revealed that toxicity and hydrophobicity are related to each other in pulmonary delivery. Here, we are reporting a chemically modified dextran having amphiphilicity and cationicity achieved by controlled grafting of stearyl amine. Two proportions of lipopolymers were synthesized and physico-chemical characterization was carried out. In-vivo evaluation of sub-acute toxicity of the synthesized lipopolymer in Sparague Dawley rat was carried out for three months. This was followed by a histological evaluation of the sacrificed animal's lung. Further, the synthesized lipopolymer was formulated with drug (Rifampicin) loaded inhalable microparticles through spray drying. The final drug formulation was tested for toxicity and proinflammatory responses in human cell lines. Dose deposition efficiency of the formulation was determined using Anderson Cascade Impactor.
Copyright © 2015. Published by Elsevier Ltd.
Pharmaceutical spray-freeze drying (SFD) includes a heterogeneous set of technologies with primary applications in apparent solubility enhancement, pulmonary drug delivery, intradermal ballistic administration and delivery of vaccines to the nasal mucosa. The methods comprise of three steps: droplet generation, freezing and sublimation drying, which can be matched to the requirements given by the dosage form and route of administration. The objectives, various methods and physicochemical and pharmacological outcomes have been reviewed with a scope including related fields of science and technology.
Copyright © 2015. Published by Elsevier B.V.
Purpose: The purpose of the study was to understand the role of particle size and shape changes in modifying agglomerate strength distribution and de-agglomeration of cohesive lactose powders. Methods: The relative de-agglomeration of three lactoses of different particle size distributions (Lactohale 201 or LH201, Lactohale 210 or LH210 and Lactohale 220 or LH220) was determined from laser diffraction particle sizing of the aerosol plume at different air flow rates. The agglomerate strength distributions were estimated by Monte Carlo simulation using the primary particle size, work of cohesion and tapped density distributions determined by laser diffraction, inverse gas chromatography and tapping apparatus, respectively. The morphology and particle shape parameters were determined by scanning electron microscopy and the Morphologi G3. Results: The estimated agglomerate strength correlated well with the de-agglomeration of all lactose samples at different air flow rates. While the work of cohesion of the lactose samples was not significantly different, the packing fraction was dependent on the proportion and shape of intermediate-sized, cohesive particles between 5.4 and 14 pm. For example, while the proportion of particles <5.4 pm was similar for all lactose samples, the proportion of intermediate-sized, cohesive particles increased in the order of LH201 < LH210 < LH220. The intermediate-sized, cohesive particles were more elongated than the <5.4 pm fraction and the extent of elongation of the lactose samples increased in the order of LH220 > LH210 > LH201. Conclusion: The study reinforced the role of agglomerate strength distributions in understanding deagglomeration of cohesive materials. Modification of particle size distributions and shape characteristics contributed to the agglomerate strength changes in the lactose samples. The study enhanced the fundamental understanding of powder de-agglomeration and provided strategic approaches that could be used to improve inhalation product performance.
Spray-freeze-drying (SFD) is an unconventional freeze drying technique that produces uniquely powdered products whilst still including the benefits of conventionally freeze dried products. SFD has potential applications in high value products due to its edge over other drying techniques in terms of product structure, quality, and the retention of volatiles and bioactive compounds. In cases where other drying techniques cannot provide these product attributes, SFD stands out despite the costs and complexities involved. This paper outlines the principles, methods, significant process parameters, particle morphology and quality aspects of SFD. Recent developments in this technique are reviewed including ultrasonic spray-freeze-drying, the application of computational fluid dynamics and mathematical modelling, and the incorporation of new technologies to improve product quality. In addition, the advantages, limitations and future scope for research in the field of SFD are discussed.
Anisotropic scaffolds with the typical structure of lamellar, aligned, and continuous pores were successfully achieved by the directional solidification of water based β-tricalcium phosphate (β-TCP) suspensions. Adjustable porosities from 49 to 82 %, tunable pore widths from 8 to 50 μm, and linked ceramic cells with wall thicknesses from 4 to 30 μm were obtained. Correlated compressive strengths reached from 0.4 MPa (82 % porosity, low solidification velocity of 10 μm/s) to 40 MPa (49 % porosity, high solidification velocity of 30 μm/s). At a given scaffold porosity the compressive strength increased by more than two times with increasing solidification velocity due to attendant structural changes. Thus, the key to control structural sizes, besides the trivial control of porosity through the water content in the initial suspension, is the control of the solidification velocity. In this study an analytical solution of the heat conduction equation was used as a novel approach to control the solidification velocity during the process. The relationship between processing conditions and resulting structure as well as between structure and mechanical properties was elucidated and discussed.
Poly(ethylene oxide) (PEO) is known for facilitating the electrospinning of biopolymer solutions, which are otherwise not electrospinnable. The objective of this study was to improve the understanding of the positive effects of PEO on the electrospinning of whey protein isolate (WPI) solutions under different pH conditions. Alterations in protein secondary structure and polymer solution properties (viscosity, conductivity, and dynamic surface tension), as induced by pH changes, significantly affected the electrospinning behavior of WPI/PEO (10% w/w: 0.4% w/w PEO) solutions. Acidic solutions resulted in smooth fibers (707 ± 105 nm) while neutral solutions produced spheres (2.0 ± 1.0 μm) linked with ultrafine fibers (138 ± 32 nm). In comparison, alkaline solutions produced fibers (191 ± 36 nm) that were embedded with spindle-like beads (1.0 ± 0.5 μm). 13C NMR and FTIR spectroscopies showed that the increase in random coil and α-helix secondary structures in WPI were the main contributors to the formation of bead-less electrospun fibers. The electrospinning-enabling properties of PEO on aqueous WPI solutions were attributed to physical chain entanglement between the two polymers, rather than specific polymer–polymer interactions. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2012
Formulating nanoparticles for delivery to the deep lung is complex and many techniques fail in terms of nanoparticle stability. Spray freeze drying (SFD) is suggested here for the production of inhalable nanocomposite microcarriers (NCM). Different nanostructures were prepared and characterized including polymeric and lipid nanoparticles. Nanoparticle suspensions were co-sprayed with a suitable cryoprotectant into a cooled, stainless steel spray tower, followed by freeze drying to form a dry powder while equivalent compositions were spray dried (SD) as controls. SFD-NCM possess larger specific surface areas (67-77 m(2)/g) and lower densities (0.02 g/cm(3)) than their corresponding SD-NCM. With the exception of NCM of lipid based nanocarriers, SFD produced NCM with a mass median aerodynamic diameter (MMAD) of 3.0±0.5μm and fine particle fraction (FPF⩽5.2μm) of 45±1.6% with aerodynamic performances similar to SD-NCM. However, SFD was superior to SD in terms of maintaining the particle size of all the investigated polymeric and lipid nanocarriers following reconstitution (Sf/Si ratio for SFD ≈ 1 versus >1.5 for SD). The SFD into cooled air proved to be an efficient technique to prepare NCM for pulmonary delivery while maintaining the stability of the nanoparticles.
Interactions between water and dextran have been investigated by measuring specific heat capacity, adiabatic compressibility, and viscosity, with dextran samples of molecular weight above 104. For these measurements, a laboratory-constructed isoperibol twin calorimeter and an ultrasonic interferometer were used. The compressibility data show the existence of the water hydrated to dextran molecules, and the amount of hydration water was determined. The partial molar heat capacity was calculated for the structural unit of the dextran molecule. In the plot of log [η] against logMw, a downward deviation from the linear relation was observed, and this was interpreted as due to branching of the dextran molecule. The amount of hydration water and the partial molar heat capacity decreased with the increasing molecular weight of dextran. The quantity ΔCP2°=CP2°−CP2 (pure state) indicates that the structural change of water caused by the dissolution of one structural unit of the dextran molecule is smaller than in the case of glucose and that the degree of the structural change of water decreases sharply with the increasing molecular weight of polymers. These results are interpreted in terms of the combination of branching and increased entanglement of the polymer chain.
Aqueous dispersions of lanthanum strontium manganite (LSM) and yttria‐stabilized zirconia (YSZ) particles were controllably freeze‐cast and then partially sintered resulting in anisotropic, hierarchically porous ceramics for Solid Oxide Fuel Cell (SOFC) cathodes. The resulting microstructures have aligned pores with a characteristic spacing (λ) between pore centers. The effect of freezing rate, slurry viscosity, and solid loading on solidification velocity and resultant microstructures was explored. Varying these parameters resulted in samples with a range of independently controllable and reproducible microstructures. Homogenous dispersion of LSM and YSZ in the freeze‐cast structures was confirmed through elemental mapping. Freezing rate was found to have a significant effect on λ while solid loading affected overall porosity and ceramic wall‐ to‐pore size ratio but had only a small influence on λ. Viscosity was found to have a complex albeit small impact on λ but a significant effect on particle dispersion and colloid stability.
Hydrodynamic volume, radius of gyration, and viscometric constants, K and a, for dextran, with a wide molecular weight range were calculated using experimental reported average-molecular weights (Mn, Mw), and intrinsic viscosity, [η], data in water and 0.05 M Na2SO4. Degree of chain branching for dextran was also determined using different procedures. This study demonstrated that hydrodynamic volume and radius of gyration of a dextran sample with Mw < 20 kDa and its linear counterpart with equal Mw are almost identical, whereas the latter parameters for a dextran sample with Mw > 20 kDa was smaller than that of its linear counterpart. Values of 0.506 in water and 0.512, 0.425 and 0.273 in 0.05 M Na2SO4 for the exponent a were obtained. A smaller value for a was obtained for a larger Mw range. Molecular weights of desirable nano-particles for various branches of nanotechnology can be estimated from a derived radius of gyration–molecular weight relationship.
Over 40% of active pharmaceutical ingredients (API) under development pipelines are poorly water-soluble drugs which limit formulation approaches, clinical application and marketability because of their low dissolution and bioavailability. Solid dispersion has been considered one of the major advancements in overcoming these issues with several successfully marketed products. A number of key references that describe state-of-the-art technologies have been collected in this review, which addresses various pharmaceutical strategies and future visions for the solubilization of poorly water-soluble drugs according to the four generations of solid dispersions. This article reviews critical aspects and recent advances in formulation, preparation and characterization of solid dispersions as well as in-depth pharmaceutical solutions to overcome some problems and issues that limit the development and marketability of solid dispersion products.
The surface microstructure will determine a number of functional properties of a frozen powder such as stickiness and flowability. In this study, cryo-SEM images were used to observe the influence of various solutes and freezing conditions had on the internal and surface microstructure of frozen droplets. A single droplet freezing method was used to simulate the physical changes taking place during a spray-freezing process. Sucrose solutions with added anhydrous milk fat (AMF) and whey protein concentrate (WPC) were investigated. The level of supercooling (nucleation temperature) significantly influenced the final microstructure of a frozen droplet. The greater the supercooling level, the larger the proportion of the droplet that has a fine cellular ice crystal structure. It was observed that a sucrose layer formed at the outer surface of sucrose solution droplets upon freezing. This could be the product of water evaporation or redistribution of sucrose during freezing. The concentrated sucrose layer showed a tendency to increase in thickness when nucleation was forced at the droplet surface. The presence of AMF and WPC at a high freezing rate, with a high droplet supercooling inhibited the formation of the surface sucrose layer, whereas at a low freezing rate with low droplet supercooling, a sucrose layer was formed with AMF fat globules and or WPC protein aggregates distributed within it. The inhibition of the formation of the sucrose surface layer could reduce the stickiness and increase the flowability of the frozen powder. Whereas, the redistribution of fat to the surface may also be a means of reducing the fat content of a frozen food powder without effecting its sensory impact. The results illustrate that both the composition and the freezing conditions will influence the functional properties of spray-frozen food powders.
Competitive adsorption between bovine serum albumin (BSA) and β-lactoglobulin (β-Lg) during spray-drying was studied and the results were compared to the adsorption of single protein at the powder surface. The study was performed with a new method using fluorescence quenching of pyrene labelled proteins at the powder surface. Comparing the single adsorption of the two proteins during spray-drying showed a similar adsorption behaviour with little preferential adsorption of one protein over the other. Analysis of the powder surface after spray-drying a mixture of BSA and β-Lg in a dextran matrix indicated that β-Lg adsorbed to the surface in preference to BSA at lower concentrations, but at higher concentrations the effect was less pronounced. When one of the proteins was spray-dried in a surplus of the second protein the adsorbed amount of the protein studied showed a strong decrease in apparent surface load at higher concentrations. However, at lower concentrations the adsorption seemed to be independent of the other protein present. This was the case for both BSA and β-Lg. In the single adsorption study of β-Lg the apparent surface load of β-Lg was measured to be 1.1mg/m2 at a concentration of 10% β-Lg in the powder.
Control of particle size and morphology has increasingly captured the attention of researchers for decades. The exploration of unique sizes and shapes as they relate to various properties has become a great quest for large field applications. To meet these demands, this review covers recent developments in particle processing. An aerosol-assisted self-assembly technique, with a spray-drying method as a representative of it, to create particles is thoroughly reviewed. Its popularity and its broad use in industry for producing particles are the main reason of this review; thus, elucidation of this method is important for the improvement of particle technology. A practical spray-drying method is described from the step-by-step process to the selection of apparatus types (merits and demerits). Elaboration of particle processing of several morphologies (sphere, doughnut, encapsulated, porous, hollow, and hairy) is discussed in terms of the selection of material types, the addition of supporting materials, and the change of process conditions. Controllable size is also discussed in terms of the adjustment of the droplet size, initial precursor concentration, and the addition of specific techniques. A comparison between a theoretical mechanism and current experimental results (over a 15-year period) are shown to clarify how particles with various sizes and morphologies are designed. This method must be considered an art rather than a science because of its advantages in creating wonderful and unique particle shapes. The performance of various particle morphologies is also demonstrated, which is essential for an understanding of the importance that shape can exert on practical use. Because the method outlined here can be broadly applied to the production of various types of functional materials, we believe that this report contributes new information to the field of chemical, material, environmental, and medical engineering.
This manuscript reports a detailed study on the ability of poly(vinyl alcohol) to act as a bio-mimetic surrogate for antifreeze(glyco)proteins, with a focus on the specific property of ice-recrystallisation inhibition (IRI). Despite over 40 years of study, the underlying mechanisms which govern the action of biological antifreezes are still poorly understood, which is in part due to their limited availability and challenging synthesis. Poly(vinyl alcohol) (PVA) has been shown to display remarkable ice recrystallisation inhibition activity despite its major structural differences to native antifreeze proteins. Here, controlled radical polymerization is used to synthesise well defined PVA which has enabled us to obtain the first quantitative structure-activity relationships, to probe the role of molecular weight and comonomers on IRI activity. Crucially, it was found that IRI activity is 'switched on' when the polymer chain length increases from 10 and 20 repeat units. Substitution of the polymer side chains with hydrophilic or hydrophobic units was found to diminish activity. Hydrophobic modifications to the backbone were slightly more tolerated than side chain modifications which implies an unbroken sequence of hydroxyls units is necessary for activity. These results highlight that although hydrophobic domains are key components of IRI activity, the random inclusion of addition hydrophobic units does not guarantee an increase in activity and that the actual polymer conformation is important.
The control of ice nucleation and growth is critical in many natural and engineering situations. However, very few compounds are able to interact directly with the surface of ice crystals. Ice-structuring proteins, found in certain fish, plants, and insects, bind to the surface of ice, thereby controlling their growth. We recently revealed the ice-structuring properties of zirconium acetate, which are similar to those of ice-structuring proteins. Because zirconium acetate is a salt and therefore different from proteins having ice-structuring properties, its ice-structuring mechanism remains unelucidated. Here we investigate this ice-structuring mechanism through the role of the concentration of zirconium acetate and the ice crystal growth velocity. We then explore other compounds presenting similar functional groups (acetate, hydroxyl, or carboxylic groups). On the basis of these results, we propose that zirconium acetate adopts a hydroxy-bridged polymer structure that can bind to the surface of the ice crystals through hydrogen bonding, thereby slowing down the ice crystal growth.
Highly porous alumina ceramics with completely interconnected pore channels were fabricated by freezing dilute alumina/camphene slurries with solid loadings ranging from 5 to 20 vol%. This method fundamentally made full use of the three-dimensional camphene dendritic network for producing interconnected pore channels and the concentrated alumina powder network for achieving dense alumina walls. Firstly, alumina/camphene slurries were prepared at 60°C using ball milling and then cast into molds at 20°C. After subliming the frozen camphene, the samples were sintered at 1400°C for 5 h. This method enabled us to freeze very dilute ceramic slurries with a low solid loading of ≤20 vol% without the collapse of the sample after sintering. As the initial solid loading decreased from 20 to 5 vol%, the porosity linearly increased from 66% to 90% with an increase in the pore size, while completely interconnected pore networks were obtained in all cases. In addition, the free surfaces of the alumina walls showed full densification after sintering even at a low temperature of 1400°C, while some pores were present in the inner regions of the alumina walls.
The surface composition of spray-dried mixtures of lactose-protein and lactose-glycine were estimated by means of electron spectroscopy for chemical analysis (ESCA). The results show that even with a low concentration of protein (0.01 wt.%) in the solution to be dried, protein starts to appear on the surface of the powder. At a protein/lactose ratio of 1/99 the protein starts to dominate the powder surface. At a protein/lactose ratio of 20/80, about 70% of the surface is covered by protein. The results are similar for the proteins sodium caseinate and bovine albumin.The spray drying of mixtures of lactose and glycine gives a different result. In this case, the surface composition of the powder reflects the composition of the mixture to be dried.The surface tensions of the solutions show that the proteins have a higher surface activity than lactose, since even a small amount of protein added to a lactose solution lowers the surface tension considerably. Glycine affects the surface tension only to a minor extent.These results show that the composition of the air-water interface of the drying droplets is reflected in the surface composition of the dried powder. In addition, scanning electron micrographs show that the changes in the powder structure when protein is added to the solution are associated with the presence of protein on the surface. When the surface coverage of protein increases, dents start to appear in the particles. The powders made from lactose-glycine solutions are highly agglomerated regardless of the glycine concentration.